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T cell functional exhaustion during chronic hepatitis B virus (HBV) infection may contribute to the failed viral clearance; however, the underlying molecular mechanisms remain largely unknown. Here we demonstrate that jumonji domain-containing protein 6 (JMJD6) is a potential regulator of T cell proliferation during chronic HBV infection. The expression of JMJD6 was reduced in T lymphocytes in chronic hepatitis B (CHB) patients, and this reduction in JMJD6 expression was associated with impaired T cell proliferation. Moreover, silencing JMJD6 expression in primary human T cells impaired T cell proliferation. We found that JMJD6 promotes T cell proliferation by suppressing the mRNA expression of CDKN3. Furthermore, we have identified platelet derived growth factor-BB (PDGF-BB) as a regulator of JMJD6 expression. PDGF-BB downregulates JMJD6 expression and inhibits the proliferation of human primary T cells. Importantly, the expression levels of JMJD6 and PDGF-BB in lymphocytes from CHB patients were correlated with the degree of liver damage and the outcome of chronic HBV infection treatment. Our results demonstrate that PDGF-BB and JMJD6 regulate T cell function during chronic HBV infection and may provide insights for the treatment strategies for CHB patients. [ABSTRACT FROM AUTHOR]